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  • Title: Novel Self-Assembled Ibrutinib-Phospholipid Complex for Potently Peroral Delivery of Poorly Soluble Drugs with pH-Dependent Solubility.
    Author: Qiu Q, Lu M, Li C, Luo X, Liu X, Hu L, Liu M, Zheng H, Zhang H, Liu M, Lai C, Song Y, Deng Y.
    Journal: AAPS PharmSciTech; 2018 Nov; 19(8):3571-3583. PubMed ID: 30209789.
    Abstract:
    As an irreversible small-molecule kinase inhibitor, ibrutinib (IBR) exhibits excellent tumor suppression in various tumor cells. However, IBR is insoluble at neutral pH and can dissolve only at low pH: thus, commercial IBR products present poor bioavailability and weakened in vivo antitumor activity. Therefore, we aimed to develop a stable IBR-phospholipid complex (IBR-PC) using egg phosphatidylglycerol (EPG) as excipients to improve the bioavailability of IBR and further enhance its antitumor effects. IBR-PC was characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XPRD), and molecular docking and simulation test, which all explained the interactions of two components. Solubility tests demonstrate that the novel formulation can maintain excellent solubility (above 5 mg/mL) at various pH levels. Storage stability tests show that no change in particle size or content of IBR-PC was observed during the experimental period. In vivo pharmacokinetic results demonstrated that the relative bioavailability of IBR-PC was a 9.14-fold improvement relative to that of IBR suspension (IBR-susp). Furthermore, IBR-PC was associated with enhanced cytotoxic activity in vitro and superior tumor growth suppression in vivo compared to that resulting from the free IBR. Thus, the proposed IBR-PC system is a promising drug delivery system that enhances the oral bioavailability of IBR, resulting in its improved in vivo antitumor effect.
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